Genetic Susceptibility to Non-Hodgkin Lymphoma - Renewal: Dramatic increases worldwide in the incidence of non-Hodgkin lymphoma (NHL) have stimulated considerable efforts to identify factors that may aid in the prevention and treatment of this disease and to further our understanding of the biological mechanisms that initiate and sustain a lymphoid malignancy. As a continuation of grant R01 CA 104682-01, the overall goal of this proposal is to identify genetic variants that are causally related to risk of NHL using DNA from two large case-control studies based in the San Francisco Bay Area: SF Bay Area NHL1 (400 cases, 800 controls) and SF Bay Area NHL2 (1,800 cases, 1,800 controls). We have made considerable contributions to the field to date in identifying genetic risk factors of NHL in multiple studies. We have identified nearly thirty genes strongly associated with NHL during the previous grant period, from a recent genome scan and through collaborations within the International Consortium of Investigators Working on NHL Epidemiologic Studies (InterLymph). These genes lie in the obesity, inflammation, hormone production and innate immunity pathways. Now, using the Illumina genotyping platform, under Aim#1, we will fine map these genes to identify true NHL risk alleles. Under Aim#2, as part of ongoing replication studies within InterLymph, we will lead the fine mapping of genes associated with NHL based on a large pooled genetic study currently underway that is being spearheaded by Dr. Skibola. Using data from a recent genome scan, in Aim#3, we will assess the influence of copy number variation on risk of NHL, which will then be confirmed in our additional NHL cases and controls. Finally, we will test the function of putatively causal polymorphisms identified through Aims 1 and 2 and perform mechanistic studies of risk alleles to gain further insights that will enhance our current understanding of mechanisms involved in lymphomagenesis. Results from these studies 1) can be translated into prevention and treatment programs aimed at reducing the public health burden of NHL worldwide;2) use already existing DNA from two NHL case-control studies;3) use already existing data from our genome scan;4) will be the first to report genetic susceptibility of NHL based on copy number variation in population studies;and 5) will support major efforts to perform replication, fine mapping and pooled analyses within the InterLymph consortium. PUBLIC HEALTH RELEVANCE: In 2008, non-Hodgkin lymphoma (NHL) will account for over 63,000 newly diagnosed cases and 20,000 associated deaths in the U.S. and over 300,000 cases and 172,000 deaths worldwide. Incidence and mortality rates have steadily increased over the last several decades, making NHL the fifth most common cancer in the U.S. An important role for family genetics has been established in causing lymphoma and common genetic variants may influence disease susceptibility. These studies will use genetics to increase our understanding of how lymphoma develops in the body and provide clues about environmental agents and lifestyle exposures that contribute to disease risk that may be translated to NHL screening, prevention and treatment programs.